Genetic susceptibility plays a major role in the development of non-insulin dependent diabetes mellitus (NIDDM). Involvement of several genes appears likely, and their identification has become feasible with recently developed methods of molecular genetics. Using a large panel of informative families, this proposal aims to find susceptibility genes for NIDDM using the candidate gene approach. The investigators will examine a series of known candidate genes which encode for proteins involved in glucose disposal in muscles as well as newly identified genes which are over- or under-expressed in muscles of NIDDM patients. The specific aims of this research proposal are to 1) Recruit and examine 90 informative families with NIDDM that have been selected to maximize power to detect susceptibility genes for NIDDM; 2) Establish EBV transformed lymphoblast cell lines for the examined family members (1200 individuals) and prepare DNA for genetic studies; 3) Genotype these members of the NIDDM families with highly informative DNA markers at four groups of candidate gene loci: I) Genes involved in glucose disposal and insulin action pathway such as: hexokinase II, glycogen synthase, insulin receptor, insulin receptor substrate-2; ii) Genes which are over- or under-expressed in muscle of patients with NIDDM such as rad and 5-10 others identified by subtraction cloning; iii) Genes known to inhibit insulin stimulated glucose uptake such as: membrane glycoprotein PC-1 and TNF-alpha; iv) Gene involved in glucose signaling in beta-cells such as: glucokinase and the alpha-1 subunit of the voltage-dependent calcium channels. 4) Determine linkage between NIDDM and the examined candidate genes using non-parametric and likelihood based methods. These investigators have obtained preliminary results which suggest that allelic variation at the rad locus contributes to the development of NIDDM in a significant subset of families. If the results are confirmed in a larger group of families, rad will be the first gene linked with the development of NIDDM. These findings will provide the bases for investigations of specific molecular defects which underlie susceptibility to NIDDM.